PROJECT SUMMARY/ABSTRACT Ovarian cancer is the second most common gynecologic cancer in the United States and the most common cause of death among women with gynecologic malignancies. Despite advances in treatment strategies, peritoneal metastasis remains the primary cause of morbidity and mortality in ovarian cancer. The National Cancer Research Institute Clinical and Translational Radiotherapy Research Working Group (CTRad) has made recommendations to address this unmet need, with an emphasis on drug?radiotherapy combinations. Recent studies suggest that intraperitoneal delivery of therapeutics, including radiotherapeutics (brachytherapy) can improve patient outcomes. Thus, this proposal is focused on the intraperitoneal delivery of mesoporous silica nanoparticles (MSNs) containing the ?? particle-emitting therapeutic radionuclide 166Ho (produced by neutron activation of stable holmium) in combination with the chemotherapeutic agent cisplatin for the treatment of ovarian cancer. The goal of this project is to advance the 166Ho-MSN product toward clinical trials by demonstrating its safety and efficacy in preclinical animal models in the treatment of peritoneal metastases of ovarian cancer when co-administered with cisplatin. The first specific aim is to optimize the dosing regimen of 166Ho-MSN-based brachytherapy when administered in combination with cisplatin chemotherapy. Intraperitoneal administration doses and schedules of 166Ho-MSNs and cisplatin combination will be optimized and compared with either cisplatin, 166Ho-MSNs, non-radioactive 165Ho-MSNs, non-nanoparticle based 166Ho or saline. Two ovarian cancer cell lines with different progression profiles will be employed. Tumor growth will be determined by bioluminescence imaging of the luciferase over-expressed ovarian cancer cells, and absorbed radiation doses to the tumors and to surrounding tissues will be calculated based upon the tissue biodistribution and degree of tumor penetration of the 166Ho-MSNs. Survival will be expressed by Kaplan-Meier analysis to evaluate the efficacy improvement of the 166Ho-MSNs-cisplatin combination treatment. The second specific aim is to assess the toxicity and safety of the non-radioactive Ho-MSNs as well as the combination chemo-brachytherapy. All tissues collected from the studies conducted under aim 1 will be evaluated histologically for toxicity assessment. In addition, two standard ISO tests will be performed as an initial assessment of the safety of the non-radioactive Ho-MSNs. These include the intracutaneous injection test in the rabbit to assess the potential of the Ho-MSNs to produce irritation, and the systemic injection test in mice to evaluate systemic responses to the Ho-MSNs following intraperitoneal injection. The demonstration of efficacy and low tissue toxicity will strongly support the planned Phase II studies (cGMP manufacture/neutron activation, GLP toxicology, immunology, biocompatibility, microbiology, etc.). There is an urgent need to improve treatments and survival in metastatic ovarian cancer. The successful outcome of this translational project is expected to address these needs through a new paradigm for treating ovarian cancer patients.